Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Sewa Rijal, Shaun Fleming, Nik Cummings, Natalie Rynkiewicz, Lisa Michelle Ooms, Nhu-Y N Nguyen, Tse-Chieh Teh, Sharon Avery, Julie McManus, Anthony Troy Papenfuss, Catriona Ann McLean, Mark Andrew Guthridge, Christina Anne Mitchell, Andrew Wei

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.
Original languageEnglish
Pages (from-to)2815-2824
Number of pages10
JournalBlood
Volume125
Issue number18
DOIs
Publication statusPublished - 30 Apr 2015

Cite this

Rijal, Sewa ; Fleming, Shaun ; Cummings, Nik ; Rynkiewicz, Natalie ; Ooms, Lisa Michelle ; Nguyen, Nhu-Y N ; Teh, Tse-Chieh ; Avery, Sharon ; McManus, Julie ; Papenfuss, Anthony Troy ; McLean, Catriona Ann ; Guthridge, Mark Andrew ; Mitchell, Christina Anne ; Wei, Andrew. / Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. In: Blood. 2015 ; Vol. 125, No. 18. pp. 2815-2824.
@article{c1d42608ce094def81275a425fbbd57e,
title = "Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML",
abstract = "Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.",
author = "Sewa Rijal and Shaun Fleming and Nik Cummings and Natalie Rynkiewicz and Ooms, {Lisa Michelle} and Nguyen, {Nhu-Y N} and Tse-Chieh Teh and Sharon Avery and Julie McManus and Papenfuss, {Anthony Troy} and McLean, {Catriona Ann} and Guthridge, {Mark Andrew} and Mitchell, {Christina Anne} and Andrew Wei",
year = "2015",
month = "4",
day = "30",
doi = "10.1182/blood-2014-09-603555",
language = "English",
volume = "125",
pages = "2815--2824",
journal = "Blood",
issn = "0006-4971",
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Rijal, S, Fleming, S, Cummings, N, Rynkiewicz, N, Ooms, LM, Nguyen, N-YN, Teh, T-C, Avery, S, McManus, J, Papenfuss, AT, McLean, CA, Guthridge, MA, Mitchell, CA & Wei, A 2015, 'Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML' Blood, vol. 125, no. 18, pp. 2815-2824. https://doi.org/10.1182/blood-2014-09-603555

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. / Rijal, Sewa; Fleming, Shaun; Cummings, Nik; Rynkiewicz, Natalie; Ooms, Lisa Michelle; Nguyen, Nhu-Y N; Teh, Tse-Chieh; Avery, Sharon; McManus, Julie; Papenfuss, Anthony Troy; McLean, Catriona Ann; Guthridge, Mark Andrew; Mitchell, Christina Anne; Wei, Andrew.

In: Blood, Vol. 125, No. 18, 30.04.2015, p. 2815-2824.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

AU - Rijal, Sewa

AU - Fleming, Shaun

AU - Cummings, Nik

AU - Rynkiewicz, Natalie

AU - Ooms, Lisa Michelle

AU - Nguyen, Nhu-Y N

AU - Teh, Tse-Chieh

AU - Avery, Sharon

AU - McManus, Julie

AU - Papenfuss, Anthony Troy

AU - McLean, Catriona Ann

AU - Guthridge, Mark Andrew

AU - Mitchell, Christina Anne

AU - Wei, Andrew

PY - 2015/4/30

Y1 - 2015/4/30

N2 - Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.

AB - Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.

UR - http://www.bloodjournal.org/content/bloodjournal/125/18/2815.full.pdf

U2 - 10.1182/blood-2014-09-603555

DO - 10.1182/blood-2014-09-603555

M3 - Article

VL - 125

SP - 2815

EP - 2824

JO - Blood

JF - Blood

SN - 0006-4971

IS - 18

ER -